Field of the Invention
The present invention relates to compositions of polyalkylene oxide hydrogels, as well as methods of making and using the hydrogel for wound healing applications. More particularly, embodiments relate to compositions comprising functionalized polyethylene glycol (PEG) in new and useful configuration hydrogels.
Description of the Related Art
Vesicants such as sulfur mustard, nitrogen mustard and half mustard are potent cytotoxic and mutagenic agents. Sulfur mustard (SM) has the chemical formula bis(2-chloroethyl) sulfide and is a well known chemical warfare agent. It was first used as such during World War I and has been subsequently used in over 10 additional conflicts.
Nitrogen mustard and half mustard are analog derivatives of SM and, just like SM, also have potential as chemical warfare agents. Half mustard (CEES) has the chemical formula 2-chloroethyl ethyl sulfide, and nitrogen mustard (NM) encompasses a class of chloroalkyl amines, the three most common species including bis(2-chloroethyl) ethyl amine (HN1); bis(2-chloroethyl) methyl amine (HN2) and tris(2-chloroethyl) amine (HN3). Many countries have been stockpiling these derivatives for use as chemical warfare agents, but none have ever been used.
The toxicity between SM, NM and CEES varies. Nevertheless, exposure to any one of these agents can cause devastating injuries to the eyes, skin and respiratory system, with the eyes being the most sensitive tissue to exposure. SM, for example, exhibits a threshold in the eyes of 12 mg·min/m3, as compared to 200 mg·min/m3 for the skin. Thus, even low doses of SM, NM, or CEES induce incapacitation, visual impairment and panic. While the molecular mechanisms for SM, NM, or CEES induced injury are unclear, these all exhibit DNA, RNA and protein alkylation and cause inflammation, tissue damage and cell death.
MMPs are a family of enzymes that enhance the action of many activating factors during inflammatory response and contribute to tissue degradation. MMP-9 has been identified as a potential target of therapy for SM, NM, and/or CEES damage since it was found that its expression and activation quantitatively increases over time in response to SM exposure. The cornea is clinically impaired by such exposure exhibiting chronic inflammation and increased MMP activity. Decreased MMP-9 activity in humans has been found to correlate with accelerated wound healing. Hence, intervention targeting of both the inflammatory response and increased protease expression could provide a therapeutic approach for the treatment of vesicant induced corneal wounds.
Doxycycline is a long acting semi-synthetic tetracycline analog, which is well recognized for its therapeutic efficacy in treating MMP mediated ocular surface diseases, such as rosacea, recurrent epithelial erosions and sterile corneal ulcerations. Doxycycline has been found to inhibit MMP-9 activity in vivo in the corneal epithelial cells of experimental dry eye as well as in vitro in human corneal epithelial cells. Treatment with doxycycline has been shown to be beneficial in attenuating acute and delayed ocular injuries caused by SM exposure. The drug is an inexpensive, FDA approved antibiotic that likely promotes wound healing by reducing inflammation and protease activity.
Minocycline is also a long acting semi-synthetic tetracycline analog that exhibits neuroprotective, anti-apoptotic, and anti-inflammatory effects. Recently, it has been shown to inhibit macrophage inflammation and T cell activation, as well as inhibiting the inflammatory effects of the enzyme 5-lipoxygenase. Much like doxycycline, minocycline also has been shown to inhibit MMP-9 activity in vivo, particularly after cerebral ischemia. It has been previously suggested that this MMP inhibitory action could be a central link for minocycline's neuroprotective, anti-apoptotic, and anti-inflammatory effects. For at least this reason, minocycline is also a good candidate for promoting wound healing.
The blood-ocular barriers, which include the blood-aqueous and blood-retina barriers protect the eye, but prevent drug distribution to the anterior and posterior chambers, limiting ocular bioavailability. Drug diffusion into the eyes from the systemic circulation is slow and inefficient. Most drugs applied to the eye surface as solutions have ocular bioavailability in the range of about 10% with most of the drug being cleared by local systemic absorption. Solutions are in contact with the eye surface for a very short period of time as the tear film quickly washes them away.
The contact time, local drug concentration and thereby duration of action can be prolonged by designing topical formulations with higher viscosities. The ideal drug delivery system for corneal wound repair should be nontoxic, transparent, easy to administer, possess rheological properties to maintain its structural integrity, provide a microbial barrier, release the drug in a controlled and sustained manner and decrease the time of wound healing. There are very few-controlled drug delivery systems reported for corneal wound repair applications. Although doxycycline and minocycline are commercially available in a wide variety of dosage formulations including tablets, capsules and suspensions, topical ocular doxycycline eye drop formulations are to this day compounded by a pharmacist. Since there are currently no ocular formulations commercially available for doxycycline, there is a critical need for a controlled release doxycycline delivery system that can be easily applied to the eye to promote wound healing.